Bretazenil is a known substance. Its preparation is described, for example, in European Patent Publication No. 59 391 which is incorporated herein by reference. The anticonvulsive and anxiolytic properties of this compound are also described in this publication.
Bretazenil has a high affinity to the benzodiazepine receptor (BZR), the modulatory part of the receptor for the amino acid GABA. GABA is an inhibiting messenger (neurotransmitter) of certain nerve cells (neurons) of the brain. The release of GABA by one type of neuron causes inhibition of the excitability of other neurons, which can manifest itself, for example, in anxiolytic, anticonvulsive, muscle relaxant or sedative-hypnotic activity. Three main types of substances have been found which bind to the BZR and which are denoted as ligands: (1) The agonists, which intensify the inhibition by GABA; (2) the so-called inverse agonists which reduce the activity of GABA; and (3) the antagonists which do not influence the activity of GABA, but which prevent its intensification or reduction by agonists or inverse agonists at the BZR (see Haefely, W., Handbook of Anxiety 3: 165-188, 1990). Substances from the three groups of ligands which are active on the BZR generally have a high affinity to this receptor, but differ by the so-called relative intrinsic effectiveness, i.e. the capability of influencing the activity of GABA. While pure antagonists occupy the BZR, but do not influence the activity of GABA, full agonists or inverse agonists produce maximum intensification or reduction of the inhibiting activity of GABA at the BZR. It is conceivable that between the extremes there are substances with different degrees of intrinsic effectiveness and that such substances would also be found. These substances behave as weak agonists or inverse agonists, but significantly weaker than the activity of the actual full agonists. Such substances are therefore partial agonists or partial inverse agonists.
It has now been found that bretazenil is one such partial agonist or partial agonist at the BZR. In animal experiments it has been established that bretazenil has a high affinity to the BZR, but bretazenil only achieves effects which correspond to those of lower dosages of benzodiazepines (BZD), for example, diazepam. The characteristic effects and side-effects of increasing dosages of a BZD such as sedation, muscle relaxation, ataxia and amnesia could not be shown or could be shown only in subtoxic dosages for bretazenil in classical animal experiments.
It has now surprisingly been found that bretazenil can induce sleep in healthy, male and female volunteers even in low dosages and that the induced sleep corresponds largely to natural sleep.